Field of the Invention
The present invention relates to compounds for use in the treatment or prevention, suppression or amelioration of a disease mediated by the ROR gamma receptor in a subject in need thereof, in particular diabetes and diabetes-related disorders, specifically type II diabetes, methods of production of such compounds, as well as methods of treatment or prevention of such diseases.
Discussion of Related Art
Worldwide, there are about 250 million people that suffer from diabetes (type I and type II) and the number is projected to double in next two decades. Type 1 diabetes is based on lack of insulin production by the pancreas. Although the causes are not entirely known, type 1 diabetes is a multi-factorial autoimmune disease that results from the specific and progressive destruction of insulin producing beta-cells in the pancreas. Typical treatment of type 1 diabetes includes (multiple) administration of insulin, which however does not cure diabetes or prevent its eventual effects such as kidney failure, blindness, nerve damage, amputations, heart attack and stroke. Even with insulin treatment, type 1 diabetes usually results in a drastic reduction in quality of life and shortens the average life span by 15 years. Type 2 diabetes, also called non-insulin dependent diabetes mellitus, is a heterogeneous disease characterized by abnormalities in carbohydrate and fat metabolism. The causes of type 2 diabetes are multi-factorial and include both genetic and environmental elements that affect beta-cell function and insulin sensitivity in tissues such as muscle, liver, pancreas and adipose tissue. As a consequence impaired insulin secretion is observed and paralleled by a progressive decline in beta-cell function and chronic insulin resistance. The inability of the endocrine pancreas to compensate for peripheral insulin resistance leads to hyperglycaemia and onset of clinical type 2 diabetes characterized by hyperglycemia, insulin resistance, absolute or relative insulin deficiency, hyperglucagonemia, and increased hepatic glucose production. However, there is still no definitive treatment for the disease.
Applicants have now surprisingly found that the retinoid-receptor related orphan receptors (ROR) may act as a central regulator of adipogenesis. The retinoid-receptor related orphan receptors consist of three family members, namely ROR alpha (Becker-Andree, Biochem. Biophys. Res. Commun. 1993, 194:1371), ROR beta (Andre et al., Gene 1998, 516:277) and ROR gamma (He et al, Immunity 1998, 9:797) and constitute the NR1F (ROR/RZR) subgroup of the nuclear receptor superfamily (Mangelsdorf et al., Cell 1995, 83:835). Applicants have shown that in particular the ROR gamma receptor, which has been linked exclusively to immunological functions, may inhibit adipogenesis and may allow protection from diet or genetically induced insulin resistance.
Thus the present invention provides compounds of the invention, in particular compounds based on a polyhydroxylated cholane skeleton, that are able to act as ROR (gamma) receptor modulators or ligands, thereby influencing the biological pathways in adipogenesis controlled by ROR (gamma), and thus may be useful for the prevention, treatment and amelioration of diabetes and diabetes-related disorders, in particular type II diabetes.